Lapachol, a compound targeting pyrimidine metabolism, ameliorates experimental autoimmune arthritis

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Peres, Raphael S. ; Santos, Gabriela B. ; Cecilio, Nerry T. ; Jabor, Valquria A. P. ; Niehues, Michael ; Torres, Bruna G. S. ; Buqui, Gabriela ; Silva, Carlos H. T. P. ; Dalla Costa, Teresa ; Lopes, Norberto P. ; Nonato, Maria C. ; Ramalho, Fernando S. ; Louzada-Junior, Paulo ; Cunha, Thiago M. ; Cunha, Fernando Q. ; Emery, Flavio S. ; Alves-Filho, Jose C.

• Tipo de documento: Artigo Científico
• Fonte: ARTHRITIS RESEARCH & THERAPY; v. 19, MAR 7 2017.
• Citações Web of Science: 6

Resumo

Background: The inhibition of pyrimidine biosynthesis by blocking the dihydroorotate dehydrogenase (DHODH) activity, the prime target of leflunomide (LEF), has been proven to be an effective strategy for rheumatoid arthritis (RA) treatment. However, a considerable proportion of RA patients are refractory to LEF. Here, we investigated lapachol (LAP), a natural naphthoquinone, as a potential DHODH inhibitor and addressed its immunosuppressive properties. Methods: Molecular flexible docking studies and bioactivity assays were performed to determine the ability of LAP to interact and inhibit DHODH. In vitro studies were conducted to assess the antiproliferative effect of LAP using isolated lymphocytes. Finally, collagen-induced arthritis (CIA) and antigen-induced arthritis (AIA) models were employed to address the anti-arthritic effects of LAP. Results: We found that LAP is a potent DHODH inhibitor which had a remarkable ability to inhibit both human and murine lymphocyte proliferation in vitro. Importantly, uridine supplementation abrogated the antiproliferative effect of LAP, supporting that the pyrimidine metabolic pathway is the target of LAP. In vivo, LAP treatment markedly reduced CIA and AIA progression as evidenced by the reduction in clinical score, articular tissue damage, and inflammation. Conclusions: Our findings propose a binding model of interaction and support the ability of LAP to inhibit DHODH, decreasing lymphocyte proliferation and attenuating the severity of experimental autoimmune arthritis. Therefore, LAP could be considered as a potential immunosuppressive lead candidate with potential therapeutic implications for RA. (AU)

• Processo FAPESP: 09/54014-7 - EMU: aquisição dos equipamentos IVIS Spectrum e microscópio de excitação por dois fótons para imagem in vivo
• Beneficiário: Enilza Maria Espreafico
• Linha de fomento: Auxílio à Pesquisa - Programa Equipamentos Multiusuários
• Processo FAPESP: 12/25075-0 - Desenvolvimento de moléculas com ação leishmanicida baseado na inibição seletiva da enzima diidroorotato desidrogenase
• Beneficiário: Maria Cristina Nonato
• Linha de fomento: Auxílio à Pesquisa - Regular
• Processo FAPESP: 12/20990-2 - Agentes anti-infecciosos: uma evolução dos estudos químico-medicinais de naftotiazóis leishmanicidas e a busca de novos agentes tuberculostáticos
• Beneficiário: Flavio da Silva Emery
• Linha de fomento: Auxílio à Pesquisa - Regular
• Processo FAPESP: 13/08216-2 - CPDI - Centro de Pesquisa em Doenças Inflamatórias
• Beneficiário: Fernando de Queiroz Cunha
• Linha de fomento: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
• Processo FAPESP: 14/50265-3 - Metabolismo e distribuição de xenobióticos naturais e sintéticos: da compreensão dos processos reacionais à geração de imagens teciduais
• Beneficiário: Norberto Peporine Lopes
• Linha de fomento: Auxílio à Pesquisa - Programa BIOTA - Temático